4-[1-(4-cyano phenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile, or letrozole, is a potent aromatase inhibitor of estrogen biosynthesis which is effective in the treatment of hormone dependent breast cancer in post menopausal women. Estrogen deprivation is most specifically achieved using inhibitors which block the last stage in the biosynthetic sequence, i.e., the conversion of androgens to estrogens by the aromatase enzyme.
Experimental studies demonstrate that letrozole substantially inhibits aromatase activity in both malignant and non-malignant breast tissues, and markedly suppresses endogenous estrogens within the breast cancer.
The last step in the synthesis of letrozole is the reaction of 4-[1-(1H-1,2,4-triazol-1-yl)methylene benzonitrile with 4-fluoro benzonitrile. There are various conditions and reagents disclosed in the prior art for this reaction, including the use of potassium tert-butoxide. All the prior art methods result in letrozole in poor yield. Additionally, the resulting letrozole product requires further purification to eliminate the impurities associated with the reaction to get letrozole with HPLC purity more than 99%.
U.S. Pat. No. 4,978,672 discloses 4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)-methyl]benzonitrile and a process for its preparation comprising reacting 4-bromomethyl benzonitrile with 1,2,4-triazole to yield 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile. 4-[1-(1,2,4-triazol-1-yl)methyl]benzonitrile is then reacted with 4-fluorobenzonitrile to give 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile (letrozole).
In the process described in '672, the reaction of refluxing 4-bromomethyl benzonitrile with 1,2,4-triazole in the presence of potassium carbonate and potassium iodide in acetone solvent (according to example 24) gives 4-[1-(1,2,4-triazolyl)methyl]benzonitrile of the formula II in an amount of 87 wt %, and 4-[4-(1,2,4-triazol-4-yl)methyl]benzonitrile of the formula III in an amount of 11 wt %, along with 2% of other impurities. The reaction of 4-bromomethyl benzonitrile with 1,2,4-triazole in a mixture of chloroform and acetonitrile (example 9) gives 4-[1-(1,2,4-triazolyl)methyl]benzonitrile of the formula II in an amount of 30 wt %, and 4-[(1,2,4-triazol-4-yl)methyl]benzonitrile of the formula III in an amount of 40 wt %, along with 20 wt % other impurities. The ratios of intended product to impurity for the prior art processes have been determined by experiment.

When the reaction mixture of the above process step is treated with 4-fluorobenzonitrile, it yields 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)-methyl]benzonitrile, a compound of formula I, and its isomer, a compound of formula IV. Thus the impurity of formula III has to be separated before treating it with 4-fluorobenzonitrile, which involves an additional step of column purification which makes the process tedious and extremely disadvantageous in large scale production.

WO 2004/076409 discloses a regiospecific process for preparation of 4-[1-(4-cyano phenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile comprising reacting 4-halomethyl benzonitrile with 4-amino-1,2,4-triazole to give 4-[(4-amino-4H-1,2,4-triazolium-1-yl)methyl]benzonitrile halide, deaminating 4-[(4-amino-4H-1,2,4-triazolium-1-yl)methyl]benzonitrile halide to give 4-[1-(1H-1,2,4-triazol-1-yl)methylene benzonitrile, followed by reacting 4-[1-(1H-1,2,4-triazol-1-yl)methylene benzonitrile with 4-fluorobenzonitrile to obtain letrozole. This application discloses the preparation of letrozole in a 3 step process which involves an additional step of purification of 4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrile bromide, thereby making the process tedious. The yield of letrozole from 4-bromomethyl benzonitrile is 35% which is low and is not economical. The yield of 4-[(4-amino-4H-1,2,4-triazolium-1-yl)methyl]benzonitrile halide is 98 to 99%, with 1 to 2% unwanted isomeric impurity (compound III).
US 2005/0209294 discloses a process for producing 4-(1H-(1,2,4-triazol-1-yl)methyl)benzonitrile, an intermediate used in the manufacture of letrozole. The application discloses a process using sodium and potassium salts of 1,2,4-triazole for preparing the compound of formula II. Following the process described in this patent application, 4-(1H-(1,2,4-triazol-1-yl)methyl)benzonitrile is obtained in a yield of about 60% with 2 to 5% of isomeric impurity (2 to 5% of compound of formula III).
Therefore, the main objective of the present invention is to provide a process for preparation of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile of formula I, with a substantially reduced amount of isomeric impurity. Another object of the present invention is to provide simple and economical process for the preparation of 4-[1-(4-cyanophenyl)-1-(1,2,4-triazol-1-yl)methyl]benzonitrile of formula I, resulting in high yields of compound I.